Browsing by Author "Wingard, John R"
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Item Open Access A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.(Stem cells translational medicine, 2024-02) Laskowitz, Daniel T; Troy, Jesse; Poehlein, Emily; Bennett, Ellen R; Shpall, Elizabeth J; Wingard, John R; Freed, Brian; Belagaje, Samir R; Khanna, Anna; Jones, William; Volpi, John J; Marrotte, Eric; Kurtzberg, JoanneStroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.Item Open Access Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants.(American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2013-09) Mauskopf, Josephine; Chirila, Costel; Graham, Jon; Gersten, Iris D; Leather, Helen; Maziarz, Richard T; Baden, Lindsey R; Bolaños-Meade, Javier; Brown, Janice MY; Walsh, Thomas J; Horowitz, Mary H; Kurtzberg, Joanne; Marr, Kieren A; Wingard, John RPurpose
The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated.Methods
A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100-180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6-month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data.Results
Estimated mean total prophylaxis and IFI-related costs associated with voriconazole versus fluconazole prophylaxis over 12 months were higher in the entire study population and among patients receiving HCT for diagnoses other than acute myeloid leukemia (AML) but were not significantly different for patients with AML. The cost per IFI avoided ($66,919) and the cost per life-year gained ($5,453) were lower among patients with AML who received voriconazole relative to the full study population. ICERs were more favorable for voriconazole over a 6-month time frame and when modeling was conducted using generic price data. Assuming a threshold value of $50,000 for one year of life gained, the calculated probability of voriconazole being cost-effective was 33% for the full study population and 85% for the AML subgroup.Conclusion
The decision model indicated that voriconazole prophylaxis was cost-effective for patients undergoing allogeneic HCT for AML.Item Open Access Effect of cord blood processing on transplantation outcomes after single myeloablative umbilical cord blood transplantation.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2015-04) Ballen, Karen K; Logan, Brent R; Laughlin, Mary J; He, Wensheng; Ambruso, Daniel R; Armitage, Susan E; Beddard, Rachel L; Bhatla, Deepika; Hwang, William YK; Kiss, Joseph E; Koegler, Gesine; Kurtzberg, Joanne; Nagler, Arnon; Oh, David; Petz, Lawrence D; Price, Thomas H; Quinones, Ralph R; Ratanatharathorn, Voravit; Rizzo, J Douglas; Sazama, Kathleen; Scaradavou, Andromachi; Schuster, Michael W; Sender, Leonard S; Shpall, Elizabeth J; Spellman, Stephen R; Sutton, Millicent; Weitekamp, Lee Ann; Wingard, John R; Eapen, MaryVariations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery.Item Open Access Factors associated with mortality in transplant patients with invasive aspergillosis.(Clin Infect Dis, 2010-06-15) Baddley, John W; Andes, David R; Marr, Kieren A; Kontoyiannis, Dimitrios P; Alexander, Barbara D; Kauffman, Carol A; Oster, Robert A; Anaissie, Elias J; Walsh, Thomas J; Schuster, Mindy G; Wingard, John R; Patterson, Thomas F; Ito, James I; Williams, O Dale; Chiller, Tom; Pappas, Peter GBACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA. METHODS: Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression. RESULTS: Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death. CONCLUSIONS: There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.Item Open Access Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?(Open forum infectious diseases, 2021-10) Wingard, John R; Alexander, Barbara D; Baden, Lindsey R; Chen, Min; Sugrue, Michele W; Leather, Helen L; Caliendo, Angela M; Clancy, Cornelius J; Denning, David W; Marty, Francisco M; Nguyen, M Hong; Wheat, L Joseph; Logan, Brent R; Horowitz, Mary M; Marr, Kieren ABackground
Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials.Methods
In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria.Results
Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1-105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially.Conclusions
The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.Item Open Access Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens.(PloS one, 2015-01) Brasier, Allan R; Zhao, Yingxin; Spratt, Heidi M; Wiktorowicz, John E; Ju, Hyunsu; Wheat, L Joseph; Baden, Lindsey; Stafford, Susan; Wu, Zheng; Issa, Nicolas; Caliendo, Angela M; Denning, David W; Soman, Kizhake; Clancy, Cornelius J; Nguyen, M Hong; Sugrue, Michele W; Alexander, Barbara D; Wingard, John RInvasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (β-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials.Item Open Access Invasive non-Aspergillus mold infections in transplant recipients, United States, 2001-2006.(Emerging infectious diseases, 2011-10) Park, Benjamin J; Pappas, Peter G; Wannemuehler, Kathleen A; Alexander, Barbara D; Anaissie, Elias J; Andes, David R; Baddley, John W; Brown, Janice M; Brumble, Lisa M; Freifeld, Alison G; Hadley, Susan; Herwaldt, Loreen; Ito, James I; Kauffman, Carol A; Lyon, G Marshall; Marr, Kieren A; Morrison, Vicki A; Papanicolaou, Genovefa; Patterson, Thomas F; Perl, Trish M; Schuster, Mindy G; Walker, Randall; Wingard, John R; Walsh, Thomas J; Kontoyiannis, Dimitrios PRecent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001-2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.Item Open Access Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database.(Clin Infect Dis, 2010-04-15) Kontoyiannis, Dimitrios P; Marr, Kieren A; Park, Benjamin J; Alexander, Barbara D; Anaissie, Elias J; Walsh, Thomas J; Ito, James; Andes, David R; Baddley, John W; Brown, Janice M; Brumble, Lisa M; Freifeld, Alison G; Hadley, Susan; Herwaldt, Loreen A; Kauffman, Carol A; Knapp, Katherine; Lyon, G Marshall; Morrison, Vicki A; Papanicolaou, Genovefa; Patterson, Thomas F; Perl, Trish M; Schuster, Mindy G; Walker, Randall; Wannemuehler, Kathleen A; Wingard, John R; Chiller, Tom M; Pappas, Peter GBACKGROUND: The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS: The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS: We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS: In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.Item Open Access Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation.(Blood, 2010-12) Wingard, John R; Carter, Shelly L; Walsh, Thomas J; Kurtzberg, Joanne; Small, Trudy N; Baden, Lindsey R; Gersten, Iris D; Mendizabal, Adam M; Leather, Helen L; Confer, Dennis L; Maziarz, Richard T; Stadtmauer, Edward A; Bolaños-Meade, Javier; Brown, Janice; Dipersio, John F; Boeckh, Michael; Marr, Kieren A; Blood and Marrow Transplant Clinical Trials NetworkInvasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.Item Open Access Relationship of race/ethnicity and survival after single umbilical cord blood transplantation for adults and children with leukemia and myelodysplastic syndromes.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2012-06) Ballen, Karen K; Klein, John P; Pedersen, Tanya L; Bhatla, Deepika; Duerst, Reggie; Kurtzberg, Joanne; Lazarus, Hillard M; LeMaistre, Charles F; McCarthy, Phillip; Mehta, Paulette; Palmer, Jeanne; Setterholm, Michelle; Wingard, John R; Joffe, Steven; Parsons, Susan K; Switzer, Galen E; Lee, Stephanie J; Rizzo, J Douglas; Majhail, Navneet SThe relationship of race/ethnicity with outcomes of umbilical cord blood transplantation (UCBT) is not well known. We analyzed the association between race/ethnicity and outcomes of unrelated single UCBT for leukemia and myelodysplastic syndromes. Our retrospective cohort study consisted of 885 adults and children (612 whites, 145 blacks, and 128 Hispanics) who received unrelated single UCBT for leukemia and myelodysplastic syndromes between 1995 and 2006 and were reported to the Center for International Blood and Marrow Transplant Research. A 5-6/6 HLA-matched unit with a total nucleated cell count infused of ≥2.5 × 10(7)/kg was given to 40% white and 42% Hispanic, but only 21% black patients. Overall survival at 2 years was 44% for whites, 34% for blacks, and 46% for Hispanics (P = .008). In multivariate analysis adjusting for patient, disease, and treatment factors (including HLA match and cell dose), blacks had inferior overall survival (relative risk of death, 1.31; P = .02), whereas overall survival of Hispanics was similar (relative risk, 1.03; P = .81) to that of whites. For all patients, younger age, early-stage disease, use of units with higher cell dose, and performance status ≥80 were independent predictors of improved survival. Black patients and white patients infused with well-matched cords had comparable survival; similarly, black and white patients receiving units with adequate cell dose had similar survival. These results suggest that blacks have inferior survival to whites after single UCBT, but outcomes are improved when units with a higher cell dose are used.Item Open Access Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.(Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020-09) Donnelly, J Peter; Chen, Sharon C; Kauffman, Carol A; Steinbach, William J; Baddley, John W; Verweij, Paul E; Clancy, Cornelius J; Wingard, John R; Lockhart, Shawn R; Groll, Andreas H; Sorrell, Tania C; Bassetti, Matteo; Akan, Hamdi; Alexander, Barbara D; Andes, David; Azoulay, Elie; Bialek, Ralf; Bradsher, Robert W; Bretagne, Stephane; Calandra, Thierry; Caliendo, Angela M; Castagnola, Elio; Cruciani, Mario; Cuenca-Estrella, Manuel; Decker, Catherine F; Desai, Sujal R; Fisher, Brian; Harrison, Thomas; Heussel, Claus Peter; Jensen, Henrik E; Kibbler, Christopher C; Kontoyiannis, Dimitrios P; Kullberg, Bart-Jan; Lagrou, Katrien; Lamoth, Frédéric; Lehrnbecher, Thomas; Loeffler, Jurgen; Lortholary, Olivier; Maertens, Johan; Marchetti, Oscar; Marr, Kieren A; Masur, Henry; Meis, Jacques F; Morrisey, C Orla; Nucci, Marcio; Ostrosky-Zeichner, Luis; Pagano, Livio; Patterson, Thomas F; Perfect, John R; Racil, Zdenek; Roilides, Emmanuel; Ruhnke, Marcus; Prokop, Cornelia Schaefer; Shoham, Shmuel; Slavin, Monica A; Stevens, David A; Thompson, George R; Vazquez, Jose A; Viscoli, Claudio; Walsh, Thomas J; Warris, Adilia; Wheat, L Joseph; White, P Lewis; Zaoutis, Theoklis E; Pappas, Peter GBackground
Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.Methods
To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.Results
There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.Conclusions
These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.Item Open Access Umbilical cord blood transplantation for children with thalassemia and sickle cell disease.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2011-09) Ruggeri, Annalisa; Eapen, Mary; Scaravadou, Andromachi; Cairo, Mitchell S; Bhatia, Monica; Kurtzberg, Joanne; Wingard, John R; Fasth, Anders; Lo Nigro, Luca; Ayas, Mouhab; Purtill, Duncan; Boudjedir, Karim; Chaves, Wagnara; Walters, Mark C; Wagner, John; Gluckman, Eliane; Rocha, Vanderson; Eurocord Registry; Center for International Blood and Marrow Transplant Research; New York Blood CenterWe examined the efficacy of unrelated cord blood (CB) transplantation in children with thalassemia (n = 35) and sickle cell disease (n = 16), using data reported to 3 registries. Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allele level) in 7 or HLA mismatched at 1 (n = 18), 2 (n = 25), or 3 loci (n = 1). Transplant conditioning was myeloablative (n = 39) or reduced intensity (n = 12). Neutrophil recovery with donor chimerism was documented in 24 patients; 11 patients developed grade II-IV acute graft-versus-host disease (aGVHD) and 10 patients, chronic GVHD (cGVHD). Overall survival (OS) and disease-free survival (DFS) were 62% and 21% for thalassemia and 94% and 50% for sickle cell disease (SCD), respectively. In multivariate analysis, engraftment rate (hazard ratio [HR] 2.2, P = .05) and DFS (HR 0.4, P = .01) were higher with cell dose >5 × 10(7)/kg. The 2-year probability of DFS was 45% in patients who received grafts with cell dose >5 × 10(7)/kg and 13% with lower cell dose. Primary graft failure was the predominant cause of treatment failure occurring in 20 patients with thalassemia and 7 patients with SCD. Primary graft failure was fatal in 5 patients with thalassemia. These results suggest that only CB units containing an expected infused cell dose >5 × 10(7)/kg should be considered for transplantation for hemoglobinopathy.Item Open Access Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial.(The Journal of antimicrobial chemotherapy, 2016-08) Hope, William W; Walsh, Thomas J; Goodwin, Joanne; Peloquin, Charles A; Howard, Alan; Kurtzberg, Joanne; Mendizabal, Alan; Confer, Dennis L; Bulitta, Jürgen; Baden, Lindsey R; Neely, Michael N; Wingard, John R; Blood and Marrow Transplant Clinical Trials NetworkBackground
Voriconazole is a first-line agent for the prevention and treatment of a number of invasive fungal diseases. Relatively little is known about the relationship between drug exposure and the prevention of invasive fungal infections.Patients and methods
A pharmacokinetic-pharmacodynamic substudy was performed as part of the BMT CTN 0101 trial, which was a randomized clinical trial comparing voriconazole with fluconazole for the prevention of invasive fungal infections in HSCT recipients. A previously described population pharmacokinetic model was used to calculate the maximum a posteriori Bayesian estimates for 187 patients. Drug exposure in each patient was quantified in terms of the average AUC and average trough concentrations. The relationship between drug exposure and the probability of breakthrough infection was investigated using logistic regression. AUC and trough concentrations in patients with and without breakthrough infection were compared.Results
Pharmacokinetic data from each patient were readily described using the maximum a posteriori Bayesian estimates. There were only five patients that had a breakthrough infection while receiving voriconazole in the first 100 days post-HSCT. For these patients, there was no statistically significant relationship between the average AUC or average trough concentration and the probability of breakthrough infection [OR (95% CI) 1.026 (0.956-1.102) and 1.108 (0.475-2.581), respectively]. P value for these estimates was 0.474 and 0.813, respectively.Conclusions
Given the very small number of proven/probable infections, it was difficult to identify any differences in drug exposure in HSCT recipients with and without breakthrough fungal infections.